9-(1-piperazinyl)-9,10-dihydro-9,10-et hanoanthracenes and their salts

ABSTRACT

R : hydrogen atom, lower alkyl, lower hydroxyalkyl, lower alkoxycarbonyl or lower hydroxyalkoxyalkyl radical or -X-Ar radical (X : lower alkylene radical - Ar : phenyl radical eventually substituted by halogen atoms, lower alkyl or lower alkoxy radicals). They are very useful substances for human therapeutics, namely as antihistaminics and antianaphylactics. Processes for the preparation of compounds of formula 1.   The compounds are new 9-(1-piperazinyl)-9,10-dihydro-9,10ethanoanthracenes and their acid addition and quaternary ammonium salts; they correspond to the formula:

United States Patent Boissier et a1.

[5 9-(1-PIPERAZI NYL)-9,l0-DIHYDRO- 9,10-ET HANOANTHRACENES AND THEIR SALTS [75] Inventors: Jacques Robert Boissier, Paris; Roger Ratouis, Saint-Cloud, both of France [73] Assignee: Societe anonyme dite: Societe Industrielle pour la Fabrication des Antibiotques (S.I.F.A.), Puteaux, France [22] Filed: Aug. 20, 1971 [21] Appl.No.: 173,685

Related U.S. Application Data [63] Continuation of Ser. No. 730,650, May 20, 1968,

abandoned.

[30] Foreign Application Priority Data June 8, 1967 France ..67109575 Sept. 6, 1967 France ..67120105 [52] U.S. Cl....260/268 PC, 260/240 K, 260/268 TR,

[51} Int. Cl. ..C07d 51/70 [58] Field of Search ..260/268 PC, 268 TR [56] References Cited UNITED STATES PATENTS 2,673,874 3/1954 Jenkins ..260/268 PC [45] March 6, 1973 3,257,404 6/1966 Fouche ..260/268 TR 3.399.201 8/1968 Schmidt ..260/268 PC 3,422,106 l/l969 Boissier et a1. ..260/268 PC 3,459,745 8/1969 Fouche ...260/268 TR 3,576,000 4/1971 Boissier ..260/268 PC Primary ExaminerDonald G. Daus Att0rneyDavis, l-loxie, Faithfull & Hapgood 57 ABSTRACT The compounds are new 9-(1 piperazinyl)-9,10- dihydro-9,10-ethanoanthracenes and their acid addition and-quaternary ammonium salts; they correspond to the formula:

R hydrogen atom, lower alkyl, lower hydroxyalkyl, lower alkoxycarbonyl or lower hydroxyalkoxyalkyl radical or X--Ar radical (X lower alkylene radical Ar phenyl radical eventually substituted by halogen atoms, lower alkyl or lower alkoxy radicals).

They are very useful substances for human therapeutics, namel as antihistaminics and antianaphylactics. Processes or the preparation of compounds of formulal.

2 Claims, No Drawings 9-(1 PIPERAZI NYL)-9, l O-DIHYDRO-Q, l O-ET HANOANTHRACENES AND THEIR SALTS This is a continuation of application Ser. No. 730,650, May 20, 1968, now abandoned.

This invention relates to new 9-( l-piperazinyl)-9,ldihydro-9,IO-ethanoanthracenes and their acid addition and quaternary ammonium salts and to the process for preparation thereof. The products according to the invention have proved to be very useful in human therapeutics namely as antihistaminics and antianaphylactics.

The new 9-(1-piperazinyl)-9,l0-dihydro-9,l0-

ethanoanthracenes according to the invention are represented'by the general formula (lg ii) [.1

wherein R represents an hydrogen atom or a lower alkyl, lower hydroxyalkyl, lower alkoxycarbonyl or lower hydroxyalkoxyalkyl radical or a XAr radical in which X is a lower saturated or not, straight or branched alkylene radical, and Ar is a phenyl radical eventually substituted by halogen atoms or lower alkyl or lower alkoxy radicals.

The terms lower alkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower hydroxyalkoxyalkyl, lower alkylene or lower alkoxy are intended to designate radicals containing not more than six carbon atoms.

According to the present invention 9-( l-piperazinyl)-9, l O-dihydro-9, l O-ethanoanthracenes of formula 1 are prepared by reacting 9,10-dibromo-9,l0-dihydroanthracene with a piperazine of formula in which R has the meaning herein before defined, in the presence of an hydrogen bromide-binding alkaline agent, then reacting the compound of formula thus obtained, in which R has the meaning cited before, with ethylene under pressure, while heating and within a solvent, and isolating the obtained compound of formula l.

The preferred conditions for carrying out the process are as follows a. 9, l 0-dibromo-9,lO-dihydro-anthracene is added to an equimolecular quantity of piperazine of formula 2 and to twice the equimolecular quantity of an alkaline agent in a solvent. The said agent may be a tertiary organic base such as triethylamine. The alkaline agent may be as well piperazine of formula 2 itself then three times the equimolecular amount of piperazine in respect with the amount of the 9,l0-dibromo-9,l0- dihydro-anthracene are used. The solvent may be an organic inert solvent as an halogenated derivative of aliphatic hydrocarbons, an aromatic hydrocarbon or carbon disulphide. The obtained compound of formula 3 is then isolated.

b. compound of formula 3 is reacted with ethylene, preferentially over a pressure range of about 30 kg/cm2 to about 200 kg/cm2 and over a temperature range of about C to about 250 C, within a solvent such as an aromatic hydrocarbon. The products are kept in contact for several hours, for instance from 10 to 60 hours. When the reaction is over, the obtained compound of formula 1 is isolated.

When the process described herein before in a has been effected within an aromatic hydrocarbon, the compound of formula 3 may be reacted directly with ethylene without isolating said compound from the reaction medium where it was prepared. The reaction with ethylene is then preferentially performed in the conditions described above in b.

The above defined process enables to obtain very easily compounds of formula 1 in which R represents a lower alkoxycarbonyl. Therefore such compounds can be used advantageously as intermediates to give com pounds of formula 1 in which R is not a lower alkoxycarbonyl. According to the invention the latter compounds can be prepared following an alternative method of the process above described, which comprises first preparing a compound of formula 1 in which R is a lower alkoxycarbonyl radical, then hydrolyzing this compound by usual means to give 9-(l-piperazinyl)-9,l0-dihydro-9, l O-ethanoanthracene of formula III and eventually treating compound of formula 4 y an halide of formula:

Hal R 5 in which R, may represent all the possible meanings of R except hydrogen and lower alkoxycarbonyl, and Hal represents a chlorine, bromine or iodine atom.

The process of this alternative method is carried outpreferably as follows a. a 9-(4-alkoxycarbonyll -piperazinyl)-9, l 0- dihydro-9,lO-ethanoanthracene is hydrolyzed by acid or alkaline aqueous or alcoholic solutions such as hydrochloric acid, or sodium hydroxide, or potassium hydroxide solutions in water, methanol, ethanol, butanol, ethylene glycol at the boiling temperature of the reaction medium during several hours. This reaction is advantageously carried out by two successive hydrolysis, one in alkaline medium, the other in acidic medium. 9-( l-piperazinyl)-9,lO-dihydro-9,10- ethanoanthracene is then isolated by usual means.

b. eventually a compound of formula is reacted with the compound of formula 4, in presence of an hydrogen halide-binding alkaline agent. The alkaline agent may be piperazine of formula 4 itself, or an alkaline hydroxide. The reaction is advantageously carried out in a solvent as an aromatic hydrocarbon, at the boiling temperature of the reaction medium. At the completion of the reaction the desired compound is isolated by usual means.

Products of formula 1 in which R represents a lower alkyl radical or a --XAr radical, X and Ar having the meaning mentioned above, may also be prepared by reacting 9-bromoanthracene with a lithium derivative of formula LlN NRz (s) in which R represents a lower alkyl radical or a X Ar radical, X and Ar having the meaning above indicated, then treating the obtained derivative of formula:

by ethylene, following the conditions described in the first process, and isolating the desired product.

Preferably the lithium derivative of formula 6 is prepared by reacting an alkyllithium or an aryllithium (such as butyllithium or phenyllithium) with a mono substituted piperazine of formula in which R; has the meaning mentioned before, within an anhydrous solvent as ether or benzene 9- bromoanthracene is reacted advan-tageously with a lithium derivative of formula 6 at the boiling temperature of the reaction medium. When the reaction is over,

the obtained compound of formula 7 is isolated by usual means. 5 9-( l-piperazinyl)-9, l 0-dihydro-9, l 0- ethanoanthracenes of formula (I) have a basic character and according to the invention their acid addition salts may be prepared by reacting mineral or organic acids with said 9-(l-piperazinyl)-9,lO-dihydro- 9,10-ethanoanthracenes, preferably in the presence of a solvent. Preference is given to anhydrous solvents such as, for instance, benzene, ethyl ether, ethanol, acetone. According to the invention, quaternary ammonium salts may be prepared by reacting quaternizing agents with said 9-(l-piperazinyl)-9,l0-dihydro-9,l0- ethanoanthracenes, preferably in the presence of a solvent. Preference is given to anhydrous solvents such as for instance ethyl ether, methyl cyanide, acetone, dioxane, methanol, ethanol. The salts can eventually be prepared without-isolating the compound of formula 1) from the reaction medium where it was obtained.

9-( l-piperazinyl)-9, l O-dihydro-9, l 0- ethanoanthracenes of formula (1) and their salts are very useful substances for human therapeutic, namely by their remarkable antihistaminic and antianaphylactic properties.

Their toxicological and pharmacological investigations have shown their great activity and outstanding interest.

The results obtained in toxicological field (lethal doses 50) and from antihistaminic activity studies have been summarized in the under mentioned table, where are shown a. lethal doses 50 determined in mice by intraperitoneal route.

b average inhibitory concentrations 50 (I.C.50)

determinated on guinea-pig isolated ileum, ac-

40 cording to Magnuss technique, expressing the antagonistic action of compounds against the contracturing action of histamine and acetylcholine.

c the numbers of unitary lethal doses of histamine antagonized in guinea-pig by subcutaneous administration of mg/kg of the tested compound the unitary lethal dose of histamine used in the ex- TABLE 5 10 4 6 A 7 2 8 i9 1 N Antihistaniinic activity in vivo 1.0. guinea-pig Number 14.1) 50 isolatvrl ileum of unitary .p. lethal luxumplu nm-v, llistu- Acvtyl- (loses of P11). 50. No. it Form m n/kg. mini. ullolinu histuminv rug/kg. 4 (-lh ll(l 1'20 ll)- 800 U. [)5 I) Illa lUll 158 10* ll) l, 000 0. 006%). 012 8 nutrition llCl. 187 3. 10 10 (300-800 0. 2-0. 5 .l (BOW- H, B1150. 500 5.10 10" 200 0.1 l1! H H (L 69 .2. l0- 5. 10- 20() 0. 2-0. 5

perimentation was 0,8 mg/kg of histamine dihydrochloride administered by intravenous route, 30 minutes after the tested compound. The number of unitary lethal doses of histamine antagonized by a compound showed the antihistaminic activity in vivo.

-- the protective efficient doses 50 (ED. 50) of compounds against a dose of 0,8 mg/kg of histamine dihydrochloride administered by intravenous route in guinea-pig, 30 minutes after the subcutaneous administration of the different doses of the tested compound. These ED. 50 showed the doses of compounds protecting 50 percent of the animals against a single lethal dose of histamine.

Owing to their very interesting pharmacological proprieties, new 9-( l-piperazinyl)-9, l 0-dihydro-9, l 0- ethanoanthracenes of general formula 1 and their acid addition and quaternary ammonium salts are very useful medicines for human therapeutic, especially as antihistaminics and antianaphylactics. They can thereby be employed in treatment of cutaneous allergic diseases (as for instance urticaria, contact dermatitis, eczema, erythema) allergic .rhinitis, allergic asthma, gastritis, and in the treatment of anaphylactic shocks.

The usual dose varies according to the utilized product, the treated patient, the concerned complaint and the selected administration route it may be for instance from 2 mg to 250 mg per day, by oral routein human beings.

As medicines new 9-( l-piperazinyl)-9,lO-dihydro- 9,10-ethanoanthracenes of general formula 1 accordin g to the invention may be employed either in the form of base or in the form of pharmaceutically acceptable acid addition or quaternary ammonium salts. Preference is given among the acid addition salts to those obtained with the following acids:hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, maleic, fumaric, succinic, tartaric, citric, benzoic, alkane sulfonics, as also to those obtained with xanthine derivatives containing an acid hydrogen and among the quaternary ammonium salts to those ob tained with alkyl halides such as, for instance, methyl chloride bromide and iodide, hydroxy alkyl halides such as for instance the 2-hydroxyethyl chloride, bromide or iodide, alkyl sulfates such as for instance dimethyl sulfate, alkyl-alkane sulfonates or alkyl-arene sulfonates such as methyl-methane sulfonate, methylbenzene sulfonate or methyl-toluene sulfonate.

The present invention is also concerned with pharmaceutical compositions which comprise as active principles one at least of the compounds of the general formula 1 and/or their acid addition salts and/or the quaternary ammonium salts. These compositions are prepared in order to be administered through digestive, parenteral or local route. They can be solid or liquid the pharmaceutical compositions are those usually employed in human medicine, as for example tablets, coated or not, capsules, solutions, syrups, suppositories, parenteral preparations, ointments, creams, gels, aerosols. They are prepared according to usual means. The active principle or principles can be incorporated with excipients which are normally employed in those pharmaceutical compositions, such as for instance, talcum, arabic gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles, animal or vegetal fatty substances, paraffin derivatives, glycols, various wetting dispersing and emulsifying agents and preservatives.

The following non limiting examples illustrate the invention. EXAMPLE 1 9-(4-methyl-l-piperazinyl)-9,l0- dihydro-9, l O-ethanoanthracene.

A. 9-( 4-methyll -piperazinyl)-anthracene Proceeding under nitrogen, 135 g (0,4 mole) of 9,10- dibromo-9,IO-dihydro-anthracene were added to a solution of 40 g (0,4 mole) of l-methylpiperazine and 81 g (0,8 mole) of triethylamine in 400 ml of chloroform. After stirring during 1 hour, the mixture was left during 12 hours at room temperature. The obtained precipitate of triethylamine hydrobromide was collected, the chloroformic solution was washed with water, dried and concentrated. The obtained oily residue was dissolved in toluene the toluenic solution was filtered, washed with water, dried and concentrated again. The obtained oily residue was stirred with pentane to give a solid which was separated by filtration. 9-(4-methyl-l-piperazinyl)-anthracene was obtained as yellow crystals. Melting point (after recrystallization from heptane) on a heating stage microscope 164 C.

Analysis C H N,

C H Calculated 82,6 7,3 Found 82,6 7,4

B. 9-(4-methyl-1-piperazinyl)-9,lO-dihydro-9, l 0- ethanoanthracene A solution of 66 g (0,24 mole) of 9-(4-methyl-lpiperazinyl)-anthracene in 450 ml of toluene was stirred during 30 hours in an autoclave at 200 C under a pressure of ethylene of kg/cm2. After cooling, toluene was driven off by concentration in vacuo, acetone was added to the solid residue which was separated by filtration, and recrystallized from acetone to give 9-(4-methyll -piperazinyl )-9, l 0-dihydro-9, l 0- ethanoanthracene as creamy white crystals. Melting point on a heating stage microscope 152 C 153 C.

Analysis C H N:

C H N Calculated 82,9 7,9 9,2 Found 82,9 8,1 9,0

EXAMPLE 2 9-( 4-methyll -piperazinyl )-9, l 0- dihydro-9, l O-ethanoanthracene Operating under nitrogen, g (0,4 mole) of 9,10- dibromo-9,IO-dihydro-anthracene were added to a solution of 40 g (0,4 mole) of l-methylpiperazine and 81 g (0,8 mole) of triethylamine in 400 ml of chloroform. After stirring during one hour, the mixture was left during 12 hours at room temperature. The obtained precipitate of triethylamine hydrobromide was collected. The chloroformic solution was washed with water, dried and concentrated. The obtained oily residue was dissolved in toluene and the obtained solution was filtered, washed with water and dried. Then, this toluenic solution was stirred during 30 hours in an autoclave at a temperature of 200 C and under a pressure of ethylene of 100 kg/cm2. After cooling, an ethanolic hydrochloric acid solution was added to the toluenic solution, the precipitate was collected, washed with ether, dried and stirred with an aqueous diluted solution of sodium hydroxide and the solid compound was collected. 9-( 4-methyll -piperazinyl )-9 ,10- dihydro-9,lO-ethanoantliracene was obtained which was identical with the compound described in B) of ex- EXAMPLE 4 ample l (creamy white crystals, melting point on a heating stage microscope 152C).

EXAMPLE 3 9-(4-methyl-l-piperazinyl)-9,10- dihydro-9 1 O-ethano-anthracene A. 9-(4-methyl-1-piperazinyl)-anthracene Operating under nitrogen, 25,7 g (0,1 mole) of 9- bromoanthracene were added to a suspension of lithium-(4-methyl-l-piperazine) obtained by mixing 25 g (0,25 mole) of l-methylpiperazine and 0,25 mole of phenyllithium in 300 ml of anhydrous ether. 200 ml of anhydrous benzene were added, ether was driven off by distillation and the mixture was boiled under reflux during 12 hours.

Water was added, then the benzenic solution was separated, dried and concentrated. The solid residue was dissolved in diluted hydrochloric acid, the obtained solution was filtered and alkalinized by adding diluted sodium hydroxyde; the obtained precipitate was separated by filtration to give 9-(4-methyl-1-piperazinyl)-anthracene which was identical with the compound described in A of example 1 (yellow crystals, melting point on a heating stage microscope 164 C).

B. 9-(4-methyl-1-piperazinyl)-9,l0-dihydro-9,l0- ethanoanthracene Proceeding as described in B of example 1, 9-(4- methyl-l-piperazinyl)-anthracene above prepared was treated by ethylene, and 9-(4-methyl-1-piperazinyl)- 9,l-dihydro-9,lO-ethanoanthracene was obtained which was identical with the compound obtained by the process described in B of example 1 (creamy white crystals, melting point on a heating stage microscope 152 C).

9-( 4-methyll piperazinyl )-9 ,10- dihydro-9, 1 O-ethanoanthracene hydrochloride 0,029 mole of dry ethanolic hydrochloric acid was added to a solution of 8 g (0,029 mole) of 9-(4-methyl- 1-piperazinyl)-9,10-dihydro-9,lO-ethanoanthracene in 50 ml of absolute ethanol. After cooling the obtained crystals were collected and recrystallized from isopropanol to give 9-(4-methyl-l-piperazinyl)- 9,10dihydro-9,lO-ethanoanthracene hydrochloride as white crystals. (Melting point on a heating stage microscope 21 1C-2l3C).

Analysis C H Cl N,

C H N Calculated 74,0 7,4 8,2 Found 73,9 7,4 8,4

Protection from an histaminic aerosol at different intervals of time after injection of the tested compound protected/tested Doses in Ahour 3 hours 24 hours s/ 3. Antianaphylactic activity tested according to Giertz and Als technique (Int. Arch. Allergy 1961, 19, 178-179). Assays were carried out first by sensitizing intraperitoneally guinea-pigs by eggalbumin, then, after three weeks, by injecting subcutaneously the tested compound at different doses and finally, 30 minutes later, injecting again intravenously eggalbumin. It was observed that a dose of 1 mg/kg of the tested compound was sufficient to protect percent of experimented animals.

EXAMPLE 5 9-(4-methyl-1-piperazinyl)-9,10- dihydro-9, l O-ethanoanthracene methyliodide The solution of 1,5 g (0,005 mole) of 9-(4-methyl-lpiperazinyl )-9, lO-dihydro-9, 1 O-ethanoanthracene and of 2 ml of methyl iodide in 30 ml of methylcyanide, was boiled under reflux during 5 minutes. After adding 1 ml of methyl iodide, the obtained mixture was left during 12 hours at room temperature. The obtained crystals were separated by filtration to give 9-(4-methyl-1- piperazinyl)-9,10-dihydro-9,10-ethanoanthracene methyliodide as white crystals. (Melting point on a sealed capillary tube after recrystallization from methanol 284 C 285 C).

Analysis C H 1 N,

C H N Calculated 59,2 6,1 6,3

Found 59,3 6,3 6,1

EXAMPLE 6 9-[4-(2-hydroxyethyl)-l-piperazinyl]- 9, l0-dihydro-9, 1 O-ethanoanthracene A. 9-[4-( 2-hydroxyethyl)-1-piperazinyl]-anthracene Following the process described in A of example 1 but using 52 g (0,4 mole) of l-(2-hydroxyethyl) piperazine instead of l-methylpiperazine, 9-[4-(2- hydroxyethyl)-l-piperazinyl]-anthracene was obtained as yellow crystals. (Melting point on a sealed capillary tube after recrystallization from'benzene 172 C 173 C).

Analysis C H N, 0

C 1-1 N Calculated 78,4 7,2 9,1 Found 78,4 7,4 9,1

B. 9-[4-(2-hydroxyethyl)-1-piperazinyl]-9 ,10-

dihydro-9 l O-etha-noanthracene Following the process described in B of example 1, but using 9-[4-(2-hydroxyethyl) -1-piperazinyl]- anthracene instead of 9-(4-methyl-l-piperazinyl)- anthracene the 9-[4-(2-hydroxyethyl)-1-piperazinyl]- 9,l0-dihydro-9,IO-ethanoanthracene was obtained as creamy white crystals. (Melting point on a heating stage microscope after recrystallization from toluene 197C- 198C).

Analysis C H N, O

C 1-1 N Calculated 79,0 7,8 8,4 Found 79,2 7,9 8,4

EXAMPLE 7 9-[4-(2-hydroxyethyl)-1-piperazinyl]- 9 l 0-dihydro-9, l O-ethanoanthracene Operating under nitrogen, g (0,4 mole) of 9,10-

dibromo-9,lO-dihydro-anthracene were added to a solution of 157 g (1,2 mole) of 1-(2-hydr0xyethyl) piperazine in 400 ml of chloroform. After stirring dur ing 1 hour, the mixture was left during 12 hours at room temperature. The obtained l-(2-hydroxyethyl) piperazine hydrobromide was collected, the chloroformic solution was washed with water, dried and concentrated. The oily residue was dissolved in 400 ml of toluene. The obtained toluenic solution was stirred during 30 hours in an autoclave at a temperature of 200 C and under a pressure of ethylene of 100 kg/cm2. After cooling, the solution was washed with water, dried, added by 4 g of decolorizing carbon, filtered and concentrated. The solid residue was recrystallized from toluene to give 9-[4-(2-hydroxyethyl)-l-piperazinyl]- 9,10-dihydro-9,IO-ethanoanthracene, which was identical with the compound obtained by the process described in B) of example 6 (creamy white crystals, melting point on a heating stage microscope 197 C 198 C). EXAMPLE 8 9-[4-(2-hydroxyethyl)-l-piperazinyl]- 9,10-dihydro-9,IO-ethanoanthracene hydrochloride Following the process described in example 4 but using 9,7 g (0,029 mole) of 9-[4-(2-hydroxyethyl)-lpiperazinyl -9 ,10-dihydro-9 1 O-ethanoanthracene instead of 9-(4-methyl- 1 -piperazinyl)-9, l O-dihydro-9, l ethanoanthracene 9-[ 4-( 2-hydroxyethyl)- 1 -piperazinyl]-9,10-dihydro-9,IO-ethanoanthracene hydrochloride was obtained as white crystals. (Melting point on a heating stage microscope 240 C 243 C).

Analysis C H Cl N, O

C H N Calculated 71,2 7,3 7,6 Found 71,4 7,4 7,6

EXAMPLE 9 9-(4ethoxycarbonyl-l-piperazinyl)- 9,10-dihydro9,IQ-ethanoanthracene Following the process described in example 2 but using 63,2 g (0,4 mole) of 1-ethoxycarbonylpiperazine instead of l-methylpiperazine, 9-(4-ethoxycarbonyl-lpiperazinyl)-9, 1 O-dihydro-9, l O-ethanoanthracene was obtained as creamy white crystals. (Melting point on a heating stage microscope 132 C).

Analysis C H, N, O,

C H N Calculated 76,2 7,2 7,7 Found 76,3 7,3 7 8 EXAMPLE l0 2 9-( l-piperazinyl)-9,10-dihydro-9,10- ethanoanthracene The solution of 3,7 g (0,01 mole) of 9-(4-ethoxycarbonyl-1-piperazinyl)-9, lO-dihydro-9 ,10- ethanoanthracene in 50 ml of concentrated hydrochloric acid was boiled under reflux during 4 hours 100 ml of water, then 70 ml of concentrated sodium hydroxide were added. The obtained precipitate was collected, dried and recrystallized from heptane. 9( l-piperazinyl )-9, l 0-dihydro-9, l O-ethanoanthracene was obtained as creamy white crystals. (Melting point on a heating stage microscope 15 1 C- 153 C).

Analysis C H N C H N Calculated 82,7 7,6 9,6 Found 82,5 7,9 9,6

EXAMPLE l1 9-(1-piperazinyl)-9,10-dihydro-9,l0- ethanoanthracene The solution of 21,4 g (0,0595 mole) of 9-(4-ethoxycarbonyl-l-piperazinyl)-9, l0-dihydro-9,10- ethanoanthracene and of 33,6 g (0,595 mole) of potassium hydroxide in 600 ml of ethanol was boiled under reflux during 24 hours. Ethanol was driven off by concentration in vacuo, the residue was treated by 600 ml of water then by chloroform. The chloroformic extracts were dried and concentrated. The thus obtained oily residue was dissolved in a mixture of 200 ml of concentrated hydrochloric acid and of ml of ethanol. The obtained solution was boiled under reflux during 15 hours, concentrated to dryness, and alkalinized by adding sodium hydroxide. The obtained precipitate was collected, dried and recrystallized from heptane to give 9-( l-piperazinyl)-9, l0-dihydro-9, l O-ethanoanthracene which was identical with the compound obtained by the process described in example 10 (creamy white crystals, melting point on a heating stage microscope l51C- 153C). EXAMPLE 12 9-(1-piperazinyl)-9,l0-dihydro-9,10- ethanoanthracene hydrochloride Following the process mentioned in example 4 but using 5 g of 9-( 1-piperazinyl)-9,10-dihydro-9,10- ethanoanthracene and 7,5 ml of a 2 N dry hydrochloric acid solution in ethanol, 9-( l-piperazinyl)-9,10- dihydro-9,l0-ethanoanthracene hydrochloride was obtained as white crystals. (Melting point in a sealed capillary tube 272 C).

Analysis C H Cl N,

C H N Calculated 73,5 7,1 8,6 Found 73,1 7,4 8,4

EXAMPLE 13 9-(4-cinnamyl-l-piperazinyl)-9,10-

dihydro-9, 1 O-ethanoanthracene The solution of 13,5 g (0,0462 mole) of 9-(1- piperazinyl )-9 ,10-dihydro-9 1 O-ethanoanthracene and of 4,6 g (0,0231 mole) of cinnamylbromide in 200 ml of anhydrous benzene, was boiled under reflux during 48 hours. 9-(1-piperazinyl)-9,10-dihydro-9,10- ethanoanthracene hydrobromide obtained was collected and the benzenic solution was concentrated. The obtained solid residue was recrystallized from heptane to give .9-(4-cinnamyl-l-piperazinyl)-9,10-dihydro- 9,10-ethanoanthracene, as creamy white crystals. (Melting point on a heating stage microscope 177 C 178 C).

Analysis C H, N,

C H N Calculated 85,7 7,4 6,9 Found k 85,5 7,5 6,8

EXAMPLE 14 9-(4-cinnamyl-1-piperazinyl)-9,l0-

dihydro-9, l 0-ethanoanthracene hydrochloride Following the process described in example 4, but using 12 g of 9-(4-cinnamyl-1-piperazinyl)-9,10- dihydro-9,l0-ethanoanthracene, 9-(4-cinnamyl-lpiperazinyl)-9,l0dihydro-9,10-ethanoanthracene hydrochloride was obtained as white crystals. (Melting point on a heating stage microscope 227 C 231 C).

Analysis C H3, Cl N,

C H N Calculated 76 78,6 7,1 6,3 Found 78,4 7,1 6,2

EXAMPLE l5 9-(4-methyl-l-piperazinyl)-9,l0-

dihydro-9, l O-ethano-anthracene 2-hydroxyethyliodide The solution of 3 g (0,01 mole) of 9-(4-methyl-lpiperazinyl )-9, l -dihydro-9, l O-ethanoanthracene and of 3 ml of 2-iodoethanol in 30 ml of methylcyanide was boiled under reflux during 2 hours. By cooling crystals of 9-(4-methyl-1 -piperazinyl)-9,l0-dihydro-9,l0- ethanoanthracene 2-hydroxyethyliodide were formed and separated by filtration. (White crystals, melting point on a heating stage microscope after recrystallization from methanol 276 C).

Analysis C H I N, O

C H N Calculated 58,0 6,1 5,9 Found 57,7 6,3 5,5

EXAMPLE l6 9-(4-methyll -piperazinyl)-9, 10- dihydro-9, l O-ethano-anthracene 2-hydroxyethylchloride The solution of 3 g (0,01 mole) of 9-(4-methyl-lpiperazinyl)-9,l0-dihydro-9,10-ethanoanthracene and of 5 ml of 2-chloroethanol in 50 ml of toluene was boiled under reflux during 48 hours. After cooling, formed crystals were separated by filtration and 9-(4- methyl-l-piperazinyl)-9,10-dihydro-9,l0- ethanoanthracene 2-hydroxyethylchloride was obtained as white crystals. (Melting point on a heating stage microscope after recrystallization from methanol :3l4C-316C).

Analysis C H Cl N, O

C H N Calculated 71,8 7,6 7,3 Found 36 71,7 7,6 7,2

EXAMPLE l7 9-(4-methyl-1-piperazinyl)-9,l0-

dihydro-9, 1 O-ethanoanthracene dimethyl sulfate The solution of 3 g (0,01 mole) of 9-(4-methyl-1- piperazinyl )-9 ,10-dihydro-9 1 OC-ethanoanthracene and of 5 ml of dimethyl sulfate in 30 ml of methyl cyanide was boiled under reflux during 2 hours. After cooling obtained crystals of 9-( 4-methyl-l-piperazinyl)- 9,10-dihydro-9,IO-ethanoanthracene dimethyl sulfate were separated by filtration (white crystals, melting point on a heating stage microscope after recrystallization from ethanol 342 C).

Tablets were prepared which correspond to the formula:

-9-( 4-methyll -piperazinyl)-9, l 0-dihydr0-9, l0-

ethanoanthracene hydrochloride 25 mg Excipient s.q. for a tablet (Excipient can be lactose, starch, talcum, magnesium stearate).

EXAMPLE 19 A syrup was prepared which corresponds to the formula:

-9-(4-methyl-l-piperazinyl)-9,10dihydro-9,l0-

ethanoanthracene mg Flavored excipient s.q. for 100 ml EXAMPLE 20 Parenteral preparations were prepared which correspond to the formula -9-( 4-methyll -piperazinyl)-9, l 0-dihydro-9, l 0- ethanoanthracene hydrochloride 25 mg Aqueous solution EXAMPLE 21 An ointment was prepared which corresponds to the formula:

-9-(4-methyll -piperazinyl)-9, l 0-dihydro-9, l 0- ethanoanthracene hydrochloride 2 g Excipient s.q. for

in which R is a member selected from the group consisting of hydrogen (except when R forms a part of a quaternary ammonium radical), lower alkyl, lower hydroxyalkyl, lower alkoxy carbonyl (except when R forms a part of a quaternary ammonium radical) and X-phenyl, in which X is selected from the group consisting of lower alkylene and lower alkenylene.

2. A compound selected from the group consisting of 9-(4-methyll -piperazinyl )-9 ,10-dihydro-9 10- ethanoanthracene and its pharmaceutically acceptable acid addition salts and mono lower alkyl and hydroxyalkyl and di lower alkyl quaternary ammonium salts. 

1. A compound selected from the group consisting of 9-(1-piperazinyl)-9,10-dihydro-9,10 ethanoanthracenes and their pharmaceutically acceptable acid addition salts and mono-lower alkyl, hydroxyalkyl and di-lower alkyl quaternary ammonium salts, said 9-(1-piperazinyl)-9,10-dihydro-9,10-ethanoanthracenes having the formula: 